The proposed change in classifications will allow physicians to improve their ability to recognize and diagnose patients and more precisely assess potential treatment effects after transplantation. Krabbe disease, also known as globoid cell leukodystrophy, is a rare autosomal recessive metabolic disorder characterized by the deficiency of galactocerebrosidase GALC , a lysosomal enzyme responsible for the hydrolysis of psychosine and galactosylceramide. The accumulation of psychosine is toxic to oligodendrocytes and Schwann cells and the failure to digest galactosylceramide leads to the formation of multi-nucleated globoid cells, causing severe demyelination, axonopathy, and neuronal death [ 1 , 2 , 3 , 4 ].
The degradation of the central and peripheral nervous systems clinically manifests as progressive neurodegeneration, spasticity, irritability, loss of vision and hearing, seizures, and premature death [ 5 , 6 , 7 , 8 ].
The incidence of Krabbe disease has been estimated as 1 in , live births [ 3 ]. However, there is some debate among experts regarding the age range for the late-infantile, juvenile, and adult phenotypes. The early-infantile form is the most common and rapidly progressing form of the disease [ 9 , 10 , 11 ].
Symptoms of the early-infantile phenotype include irritability, regression of psychomotor development, feeding difficulties and, as the disease progresses, hypertonicity, seizures, loss of vision and hearing, and early death [ 9 , 10 , 11 ].
Symptoms of the late-infantile phenotype include psychomotor regression, ataxia, irritability and loss of vision [ 12 , 13 , 14 ]. The juvenile phenotype is characterized by loss of vision and psychomotor regression. Patients with the adult phenotype may have a normal life span but will slowly develop progressive spastic paraparesis or gait abnormalities [ 10 , 14 , 15 ].
Although more than pathogenic variants of the GALC gene have been reported in the Human Gene Database, only a limited number of genotype-phenotype relationships have been established [ 14 ]. For example, at least 86 infantile pathogenic variants have been identified; however, for many of the 86 variants, there is no report as to whether they correlate specifically with the early-infantile or late-infantile phenotype [ 12 , 15 , 16 ].
To date, few natural history studies describing the clinical and biochemical characteristics of Krabbe disease have been published and the majority are based on retrospective and nonstandardized data.
The first case series describing the infantile phenotypes was published in by the Danish clinician Knud Krabbe [ 17 ]. In , the first large cohort of patients was described by Hagberg et al. Although more recent reports by Alodsari et al. Conversely, a recent retrospective study by Zhao et al. For example, of the 12 late-infantile patients included in Duffner et al. Thus, there is an overwhelming need for prospective natural history studies that report specifically on phenotypes with onset after 6 months of age.
The only treatment currently available for Krabbe disease is hematopoietic stem cell transplantation HSCT , which can favorably alter the natural course of the infantile subtypes if performed early enough in the disease progression [ 21 , 22 , 23 , 24 ].
Mandated newborn screening NBS programs for Krabbe disease have been implemented in several states throughout the U. Depending on the enzyme activity level, infants are classified as being at high or moderate risk of developing disease. Some states also perform genetic analysis and measure psychosine levels to determine which individuals are at risk of developing the early-infantile form of the disease [ 25 , 26 , 27 , 28 ].
Although psychosine levels in dry bloods spots DBS have been shown to function as an effective predictor of disease progression in early-infantile Krabbe patients, there is less data in the literature describing correlations between psychosine levels and later onset phenotypes [ 29 ].
As a result of our lack of knowledge regarding correlations between genotype, GALC activity, psychosine levels, and disease progression, many newborns categorized as high risk require continued monitoring so they can be immediately evaluated for HSCT eligibility before they become too advanced to benefit from treatment. Thus, until precise biochemical and genotype-phenotype correlations can be established, natural history data will function as the main instrument in monitoring individuals who will develop disease following a positive NBS screening.
In addition, natural history studies will provide the predominate means for evaluating the efficacy of newly development treatments, such as gene therapy and enzyme replacement therapy [ 30 , 31 ]. Given the gaps in our knowledge, the intention of our study was to longitudinally describe the physical characteristics, signs, symptoms, and neurodevelopmental involvement in children diagnosed with Krabbe disease who had onset between 6 and 36 months of age.
The patients were evaluated at a single site and followed throughout the course of their disease, allowing for internal consistency between the observations. Multiple standardized tests in all areas of development were performed using a prospectively designed protocol.
Growth parameters were measured at every visit, and brain magnetic resonance imaging MRI and other neurophysiological analyses were carried out at baseline and longitudinally, when appropriate. Altogether, this is the largest and most comprehensive prospective study of Krabbe patients with onset between 6 and 36 months of age. This prospective cohort study included patients diagnosed with Krabbe disease who were evaluated at the Program for the Study of Neurodevelopment in Rare Disorders NDRD between January and September and had disease onset between 6 and 36 months of life.
Diagnoses were made by measuring GALC activity in white blood cells or fibroblasts, done at the Lysosomal Diseases Testing Laboratory at Jefferson Medical College, and were confirmed by genetic analysis. However, since genetic analysis was not used consistently for diagnosis until approximately , most patients diagnosed prior to lack genetic data.
Children were evaluated following a comprehensive protocol of standardized testing designed by a multidisciplinary team for longitudinal follow-up at a single site [ 32 ]. At each clinic visit, a team of neurodevelopmental pediatricians, neurophysiologists, speech pathologists, audiologists, physical therapists, and psychometricians evaluated the patient for approximately 4—6 h.
The neurodevelopmental tests included a physical and neurological exam for evaluation of signs and symptoms of disease, growth, mobility, adaptive behavior, cognitive behavior, physical characteristics, sensory function, and speech and language skills. As part of the standardized protocol, parents completed a questionnaire that asked about birth history, early signs of disease, development, and behaviors, including emergence of independent-adaptive behaviors.
Patient outcomes were compared to the norms of typically developing children [ 32 ]. Axial bold, diffusion, and susceptibility images were also obtained. MRI scans were interpreted by an experienced neuroradiologist and evaluated for any abnormalities. NCV motor responses were measured in the peroneal, tibial, and ulnar nerves, and sensory responses were measured in the sural and median nerves.
NCV responses were considered abnormal if they showed prolongation of distal and F-wave latencies, low amplitude, or no evoked response. Flash visual evoked potentials VEP were considered abnormal if the P wave was absent. CSF was obtained by lumbar puncture while the patient was under general anesthesia for MRI or local anesthesia.
Total CSF protein was determined by tandem mass spectrometry. Patients with onset between 9 and 12 months were split into two groups, those with a severe phenotype and those with a less severe phenotype; the two groups were compared in clinical variables. The ten most relevant markers of disease were selected by a group of experts in Krabbe disease. Severity scores were generated by summing the total number of markers observed in each patient. Survival curves were estimated using the Kaplan—Meier method.
All other surviving patients were censored on September 2, Clinical growth charts were created based on the published Centers for Disease Control growth charts [ 38 ].
AE scores are ideal for longitudinal analysis in neurodegenerative disorders, as they can be used to ascertain whether a child is gaining or losing skills over time [ 32 ]. Using SAS 9. To account for repeated evaluations, patient age was entered as a random variable. Group specific rates of development were calculated using post-estimation procedures. Differences between the group rate and normal development were then examined for significance.
The 35 patients evaluated in this study included 26 boys and 9 girls between the ages of 2 and 84 months 2 black, 2 Asian, 30 white, and one not reported. For 15 children, only the baseline evaluation was available since these patients subsequently underwent HSCT. Nine children were lost to follow-up for reasons related to travel or financial difficulties. The average age at diagnosis was Mean GALC activity was 0.
The average delay between appearance of initial symptoms and diagnosis of Krabbe disease was approximately 4. Three patients were asymptomatic at the time of diagnosis and were diagnosed because of their family history. Sixteen of the children developed neonatal difficulties; eight presented with multiple difficulties.
Because 3 patients were diagnosed due to family history and immediately underwent HSCT while still asymptomatic, data on initial signs and symptoms was only available for 32 of the 35 patients.
Of the 32 symptomatic patients in the study, 23 presented with initial signs or symptoms of disease between 6 and 12 months, and 9 presented after 12 months of life. In 6 of the children with feeding difficulties, a gastrostomy tube had been placed prior to their baseline evaluation.
After the initial evaluation, gastrostomy tube placement was recommended for 15 more children. Ages at which common symptoms appear in children with Krabbe disease.
The red diamond represents the median age at which the symptom began. The lines show the minimum and maximum ages that the symptom began. Symptoms that were used in creating the severity index are designated with asterisks. Following onset, the earliest symptoms in this patient group were gastrointestinal reflux, ear infections, and axial hypotonia, followed by feeding difficulties, constipation, appendicular hypertonia, and staring episodes.
As the disease progressed, visual difficulty, apneic episodes, seizures, and temperature instability became more common Fig. Most children had height and weight measurements below the 50th percentile. Five patients had a weight more than two standard deviations below the population mean during one or more visits, and 2 had a height more than two standard deviations below the population mean. In contrast, no patient had a head circumference measurement greater or lesser than two standard deviations from the mean Fig.
Height, weight, and head circumference of boys and girls with Krabbe disease. The x axis shows the patient's age in years and the y axis shows the height in centimeters. Each circle depicts an individual measurement; lines connecting circles show multiple measurements for an individual child. Results of the Kaplan—Meier analysis indicate the median survival time is 6. Kaplan—Meier curve of overall survival. The overall median survival was 6. The x axis shows age in years and below the number of patients at risk for an event.
The y axis probablity of survival. The three symptomatic children who did not present with axial hypotonia did not become symptomatic until after 2 years of age. DTR responses were not assessable for 3 children because of irritability or lack of cooperation. Visual difficulties were apparent in 12 children. Vision deterioration was observed in 9 of the 10 children longitudinally evaluated. Three children presented with cortical blindness. Of these 3, two experienced vision loss preceding changes in muscle tone, and one experienced vision loss following changes in muscle tone.
One child with abnormal VEP was asymptomatic at the time of assessment. Results of baseline hearing tests were available for 27 patients; none had hearing loss at the time of diagnosis. Two of the children with abnormal recordings were asymptomatic upon evaluation. The most common abnormality was prolongation in latencies that progressed from wave I to wave V from the auditory nerve towards the brainstem.
Gait was abnormal in all children who learned to walk. Most children rapidly lost previously achieved milestones after disease onset. Cognitive function, adaptive behavior, expressive and receptive language, and motor development were evaluated for each patient.
As a whole, patients in the study scored significantly lower than age-matched controls in all developmental domains other than expressive language. Developmental progression of children with Krabbe disease from birth to 8 years of age. Age-equivalent scores i.
Close up of developmental progression of children with Krabbe disease, from birth to 3 years of age. Cognitive function was assessed using standardized protocols that tested the ability to listen, solve visual problems, and perform simple tasks. While some children regressed in development very quickly, others had developmental quotients between the 5th and 95th percentiles. However, all children evaluated longitudinally eventually fell below the 5th percentile in cognitive development by 40 months of age Fig.
Only 1 child acquired new cognitive skills after the baseline evaluation. The central nervous system is made up of the nerves within the brain and spinal cord and is the primary control center of the body. Individuals affected by this disorder have a deficiency of the GALC enzyme, which disrupts the production of myelin.
Myelin is the insulating sheath that surrounds and protects the nervous system, and is needed for the rapid transmission of information to and from neurons throughout the body. Communication with the brain and nervous system becomes restricted or lost, resulting in progression of the disease. This results in a loss of the ability to walk, speak, swallow, cough, and more. The rate of progression depends on what form of the disease the individual has; however, as Krabbe advances it encompasses all aspects of bodily function and is a fatal disorder.
Although there is currently no cure for Krabbe, it is treatable. With proactive, comprehensive medical care the symptoms of Krabbe can be well-managed to give the individual the best quality of life possible. Furthermore, through Krabbe newborn screening, affected children have the opportunity to benefit from lifesaving treatment to stop disease progression. Krabbe Disease is a genetic, or inherited, disorder and is also classified as an autosomal recessive disorder.
This means that if both parents are carriers of the disease, each child they conceive will have a 1 in 4 chance of developing Krabbe. See illustration below. If both parents are carriers of Krabbe Disease, each child has a 1 in 4 chance of being affected. Krabbe is diagnosed through a series of tests. Oftentimes a blood test is used to determine the level of GALC enzyme activity. Although newborn screening for Krabbe is available in some states and through Supplemental Newborn Screening , it is not a diagnostic test.
However, newborn screening can lead to a proper and early diagnosis upon confirmatory testing. If your child had a positive newborn screen for Krabbe, click here. No matter what form of Krabbe an individual is diagnosed with, optimal care is of timely importance. The Leukodystrophy Care Network LCN was established to provide individuals with the best quality of care at specialized centers across the country.
For more information and to find a Leukodystrophy Care Center nearest you, please visit the Leukodystrophy Care Network page. The Early Infantile form of Krabbe Disease is the most severe. In less common cases, signs and symptoms can develop in childhood, adolescence or even adulthood.
There are currently no approved therapies that reverse the effects of Krabbe disease. Current approaches to Krabbe disease involve targeted management of specific symptoms and interdisciplinary collaboration. For Patients. Krabbe Disease. What is Krabbe disease? What are lysosomes and what do they do?
0コメント